Abstract This proposal addresses the relationship between African American (AA) and basal-like breast cancers, obesity, and environmental factors through a novel metabolically-regulated pathway that we have recently shown drives aggressive tumor cell behaviors. Combining in vitro studies with patient biopsy data and computational analyses, we will characterize the regulation and function of the widely expressed lipolysis stimulated lipoprotein receptor (LSR) in normal and transformed breast cells and tissue. LSR is a multifunctional protein known to mediate the endocytosis of lipoproteins and hydrophobic environmental toxicants such as benzo[?]pyrene in hepatocytes. Intriguingly, LSR is enriched at cell junctions and we are the first to show LSR is frequently translocated to the cell nucleus of non-surviving breast cancer (BrCa) patients. The function and underlying molecular mechanisms for these observations are unknown. Of note, studies show bodily accumulation of toxicants obtained through the diet promotes obesity and inflammation, and toxicant bioaccumulation higher in AAs and in low-income communities. Thus, we hypothesize that LSR expression and/or activity enhances aggressive BrCa phenotypes via modulation of cellular bioenergetics, toxicant bioaccumulation, and altered signal transduction and transcriptome regulation, thereby contributing to cancer disparities and poor patient outcome. In support, we recently demonstrated that LSR increases BrCa proliferation and migration, and enhances cancer stem cell-like and chemotherapeutic resistance features. Overexpression of LSR in a claudin-low BrCa cell line restores expression of genes involved in transformation, tumorigenesis, and tight junctions, thereby reverting these cells to other BrCa subtypes. Our pilot data show high LSR levels are significantly correlated with basal-like tumors, AA ethnicity, and diet-induced obesity. Our preliminary data also demonstrate that membrane-localized LSR mediates lipid endocytosis, thereby shifting cellular bioenergetics, while nuclear LSR binds DNA and was significantly associated with patient mortality in a pilot set of BrCa biopsies. To advance these preliminary studies we propose a dual approach, which includes delineating LSR's role in driving aggressive BrCa behaviors together with defining the molecular mechanisms of toxicant uptake and promotion inflammation in breast tissue. Specifically, we aims to (1) identify the LSR- driven pathways exploited during BrCa progression and the generation of aggressive cell behaviors, and (2) define the mechanisms of LSR-mediated lipid and toxicant uptake in BrCa cells, and the resultant effects on cancer bioenergetics and cell physiology. Our proposal may shed light on LSR as a biological link between obesity, inflammation, cancer disparities, and BrCa physiology. Novel knowledge obtained from the proposed studies will provide critical insight into the biological basis of dietary influences on breast cancer and may identify the LSR as a novel therapeutic target.